A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people

Pavlina Plevova; Jana Indrakova; Judy Savige; Petra Kuhnova; Petra Tvrda; Dita Cerna; Sarka Hilscherova; Monika Kudrejova; Daniela Polendova; Radka Jaklova; Martina Langova; Helena Jahnova; Jana Lastuvkova; Jiri Dusek; Josef Gut; Marketa Vlckova; Pavla Solarova; Gabriela Kreckova; Eva Kantorova; Jana Soukalova; Rastislav Slavkovsky; Jana Zapletalova; Tomas Tichy; Dana Thomasova

doi:10.3389/fmed.2023.1096869

A founder COL4A4 pathogenic variant resulting in autosomal recessive Alport syndrome accounts for most genetic kidney failure in Romani people

Front Med (Lausanne). 2023 Feb 8:10:1096869. doi: 10.3389/fmed.2023.1096869. eCollection 2023.

Authors

Pavlina Plevova^{1

2}, Jana Indrakova¹, Judy Savige³, Petra Kuhnova¹, Petra Tvrda¹, Dita Cerna¹, Sarka Hilscherova¹, Monika Kudrejova¹, Daniela Polendova⁴, Radka Jaklova⁴, Martina Langova⁵, Helena Jahnova⁶, Jana Lastuvkova⁷, Jiri Dusek⁸, Josef Gut⁹, Marketa Vlckova¹⁰, Pavla Solarova¹¹, Gabriela Kreckova¹², Eva Kantorova¹³, Jana Soukalova¹⁴, Rastislav Slavkovsky¹⁵, Jana Zapletalova¹⁶, Tomas Tichy¹⁷, Dana Thomasova¹⁰

Affiliations

¹ Department of Clinical and Molecular Pathology and Medical Genetics, University Hospital Ostrava, Ostrava, Czechia.
² Department of Biomedical Sciences, Faculty of Medicine, University of Ostrava, Ostrava, Czechia.
³ Department of Medicine (Melbourne Health and Northern Health), The University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia.
⁴ Department of Medical Genetics, Faculty of Medicine in Plzeň, Charles University and University Hospital Plzeň, Plzeň, Czechia.
⁵ Department of Medical Genetics, Thomayer University Hospital, Prague, Czechia.
⁶ Department of Pediatrics, Third Faculty of Medicine, Charles University and University Hospital Královské Vinohrady, Prague, Czechia.
⁷ Department of Medical Genetics, Krajská zdravotní, a.s., Masaryk Hospital in Ústí nad Labem, Ústí nad Labem, Czechia.
⁸ Department of Pediatrics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.
⁹ Department of Pediatrics, Hospital Česká Lípa, Česká Lípa, Czechia.
¹⁰ Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czechia.
¹¹ Department of Medical Genetics, University Hospital Hradec Králové, Hradec Králové, Czechia.
¹² Department of Medical Genetics, Gennet, s.r.o., Liberec, Czechia.
¹³ Department of Medical Genetics, Hospital České Budějovice a.s., České Budějovice, Czechia.
¹⁴ Department of Medical Genetics and Genomics, University Hospital Brno, Brno, Czechia.
¹⁵ Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia.
¹⁶ Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia.
¹⁷ Institute of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacký University Olomouc, Olomouc, Czechia.

Abstract

Introduction: Romani people have a high prevalence of kidney failure. This study examined a Romani cohort for pathogenic variants in the COL4A3, COL4A4, and COL4A5 genes that are affected in Alport syndrome (AS), a common cause of genetic kidney disease, characterized by hematuria, proteinuria, end-stage kidney failure, hearing loss, and eye anomalies.

Materials and methods: The study included 57 Romani from different families with clinical features that suggested AS who underwent next-generation sequencing (NGS) of the COL4A3, COL4A4, and COL4A5 genes, and 83 family members.

Results: In total, 27 Romani (19%) had autosomal recessive AS caused by a homozygous pathogenic c.1598G>A, p.Gly533Asp variant in COL4A4 (n = 20) or a homozygous c.415G>C, p.Gly139Arg variant in COL4A3 (n = 7). For p.Gly533Asp, 12 (80%) had macroscopic hematuria, 12 (63%) developed end-stage kidney failure at a median age of 22 years, and 13 (67%) had hearing loss. For p.Gly139Arg, none had macroscopic hematuria (p = 0.023), three (50%) had end-stage kidney failure by a median age of 42 years (p = 0.653), and five (83%) had hearing loss (p = 0.367). The p.Gly533Asp variant was associated with a more severe phenotype than p.Gly139Arg, with an earlier age at end-stage kidney failure and more macroscopic hematuria. Microscopic hematuria was very common in heterozygotes with both p.Gly533Asp (91%) and p.Gly139Arg (92%).

Conclusion: These two founder variants contribute to the high prevalence of kidney failure in Czech Romani. The estimated population frequency of autosomal recessive AS from these variants and consanguinity by descent is at least 1:11,000 in Czech Romani. This corresponds to a population frequency of autosomal dominant AS from these two variants alone of 1%. Romani with persistent hematuria should be offered genetic testing.

Keywords: Alport syndrome; Romani; consanguinity; end-stage kidney failure; hearing loss; hematuria; proteinuria.

Copyright © 2023 Plevova, Indrakova, Savige, Kuhnova, Tvrda, Cerna, Hilscherova, Kudrejova, Polendova, Jaklova, Langova, Jahnova, Lastuvkova, Dusek, Gut, Vlckova, Solarova, Kreckova, Kantorova, Soukalova, Slavkovsky, Zapletalova, Tichy and Thomasova.

Grants and funding

This work was supported by the Ministry of Health of the Czech Republic–Conceptual Development of Research Organizations, Faculty Hospital of Ostrava (IP/RVO-FNOs/2015), and by the Czech Health Research Council (NV19-06-00443).